It is well established that a consequence of aging is an increased risk of infection related diseases and death. However, most work to date on aging and resistance to viral disease is correlative, because it does not reproduce the condition of increased susceptibility to a viral disease following a primary infection with naturally pathogenic viruses. We have previously shown that during infection with the mouse pathogen ectromelia virus (ECTV), young C57BL/6 (B6) mice survive the infection without symptoms of systemic disease because their natural killer cells (NKC) migrate to the draining lymph node (D-LN) and curb viral dissemination. Conversely, aged B6 mice succumb to the infection because their NKC fail to migrate to the D-LN and the virus spreads rapidly to vital organs. Further, we showed that the lack of NKC migration is intrinsic to the NKC, because adoptively transferred NKC from aged mice did not accumulate in the D-LN of young hosts, while NKC from young mice accumulated in the D-LN of aged hosts, protecting them from lethality. Thus, we established a direct link between migration defects of NKC in the aged and decreased resistance to an infection. More recently, we determined that the NKC in aged mice are deficient due to their improper maturation in the bone marrow. We will now follow up these observations in two Specific Aims. In Aim 1, we will determine why the migration of NKC is impaired, identify other defects of NKC in aged mice and determine the generality of our findings. In Aim 2, we will investigate why NKC in aged mice fail to properly mature in the bone marrow. Because many infectious diseases in humans spread systemically via LNs and NKC-deficient patients have significantly increased incidence of viral infections, it is possible that a defective NKC maturatin and migration also contributes to the increased susceptibility of older people to at least some viruses. Our mouse model provides a unique avenue to investigate NKC dysfunctions with strong potential to advance our knowledge on causes of increased susceptibility to viral disease that we believe should be translatable to humans.